Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000419.4(ITGA2B):c.1073G>A (p.Arg358His)

Curation Version - 1.2
Curation History
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CA115839

2896 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a6fd9573-676f-4b4d-bbd9-49eea0ffdd23

Approved on: 2021-03-05

Published on: 2021-08-20

HGVS expressions

NM_000419.4:c.1073G>A

NM_000419.4(ITGA2B):c.1073G>A (p.Arg358His)

NC_000017.11:g.44383630C>T

CM000679.2:g.44383630C>T

NC_000017.10:g.42460998C>T

CM000679.1:g.42460998C>T

NC_000017.9:g.39816524C>T

NG_008331.1:g.10876G>A

ENST00000262407.6:c.1073G>A

ENST00000648408.1:n.504G>A

ENST00000262407.5:c.1073G>A

ENST00000592226.5:n.313G>A

NM_000419.3:c.1073G>A

NM_000419.5:c.1073G>A

Pathogenic

PM2_Supporting PM3_Strong PP4_Strong

PS3 PP3 PM5

Evidence Links 5

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.1073G>A (p.Arg358His) variant has been reported, in the homozygous state, in at least four probands (PMIDs: 8883261, 25728920, 19691478, 7706461) and once in a compound heterozygous case (PMID: 21557682), several of whom meet all diagnostic criteria for a phenotype highly specific to GT. This variant is absent from ExAC and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3_strong, and PP4_strong.

PM2_Supporting

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PM3_Strong

This variant has been reported in the literature in at least 4 homozygotes (PMIDs: 19691478, 8883261, 25728920, 7706461). As well as one compound heterozygote with pathogenic variant Gly412Arg (PMID: 21557682).

The proband is homozygous for Arg358His. 0.5pt PubMed:8883261

Patient GT45 is homozygous for Arg358His. 0.5pt PubMed:19691478

Patient GT26 is homozygous Arg358His as a result of consanguinity. PubMed:25728920

Patient KJ is homozygous for Arg358His (reported as Arg327His) as a result of consanguinity. PubMed:7706461

PP4_Strong

At least five GT patients have been described in the literature with the Arg358His variant, at least 1 of them (PMID: 25728920) meets the criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

The homozygous proband, Mila-1, has easy bruising and the expected platelet aggregation results with an absent response to ADP, collagen, and arachidonic acid but a normal response to ristocetin. Flow cytometry showed 25% surface expression on platelets. Normal platelet count was not reported. PubMed:8883261

The proband meets all the GT criteria. Bleeding symptoms include epistaxis, menorrhagia, spontaneous hematoma, and purpura (reported in PMID: 3762006). She has a normal platelet count, absent aggregation to ADP, arachidonic acid and collagen but a normal ristocetin response (reported in PMID: 25728920). There is 10-15% surface expression of αIIb‐β3 on the platelets (reported in review PMID: 23929305 and as GT11 in PMID: 25728920) with residual protein by Western blot. PubMed:21557682

Homozygous patient GT45 meets all the GT diagnostic criteria. There is a history of mucocutaneous bleeding, absent or reduced aggregation in response to ADP, ADR, AA and collagen and normal aggregation with ristocetin, normal platelet size, normal platelet count and no other platelet function defects. Only trace amounts of protein were detected by Western blot. PubMed:19691478

Homozygous patient GT26 had a history of mucocutaneous bleeding (epistaxis and easy bruising) and a WHO bleeding score of 4. There was much reduced platelet aggregation with at least three agonists but normal ristocetin-induced aggregation. Severely reduced (<5%) platelet expression of alphaIIb-beta3 was confirmed by flow cytometry. No mention was made of platelet count. PubMed:25728920

Homozygous patient KJ meets all the GT diagnostic criteria. Bleeding phenotypes include easy bruising and gingival bleeding. There is a normal platelet count and the expected aggregometry results with absent response to ADP, epinephrine, arachidonic acid, and collagen but normal response to ristocetin. Surface expression, measured by flow cytometry is 7-10% of normal levels and by immunoblot GPIIb is undetectable and GPIIIa at <10% normal. PubMed:7706461

PS3

As measured by flow cytometry, CHO cells stably transfected with cDNA encoding WT GPIIIa and His358GPIIb had a drastic reduction in the percent of cells with surface expression (<10%) compared to WT GPIIb. However, this evidence was not used to support PS3 at any level of strength because the level of αIIbβ3 cell surface expression was not measured, only whether cells were positive or negative for surface αIIbβ3.

The Arg358His GPIIb was cotransfected with WT GPIIIa into Cos-7 cells which were then subjected to immunoprecipitation analysis, showing greatly reduced levels of the mature GPIIb-GPIIIa complex compared to WT. This was evidenced by the coimmunoprecipitation of both subunits by AP3, but the immunoprecipitates contained reduced to nondetectable levels of the mature GPIIb heavy chain. Immunoprecipitation was not performed to look specifically at surface expression. Additionally, pulse-chase experiments were also performed, demonstrating reduced to non-detectable levels of mature GPIIb. PubMed:7706461

PP3

SIFT (damaging), PolyPhen (probably damaging), and MutationTaster (disease causing automatic) support a deleterious effect. REVEL score of 0.584 is below the >0.7 threshold.

PM5

Arg358Cys (ClinVar 426669, VUS) has also been identified at the same amino acid residue but has only been assessed to be a VUS by the ClinGen Platelet Disorders VCEP and is not considered here to avoid circularity.

Curation History

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